Ronald Tutrone

Multicentre prospective crossover study of the ‘prostatic urethral lift’ for the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia

To assess the clinical effect of the ‘prostatic urethral lift’ (PUL) on lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) through a crossover design study.

ARN-509 in men with metastatic castration-resistant prostate cancer (mCRPC).

48 Background: ARN-509 is a novel second-generation anti-androgen that binds directly to the ligand-binding domain of the androgen receptor, impairing nuclear translocation and DNA binding. The Phase II portion of a multicenter Phase I/II study is evaluating the activity of ARN-509 in 3 distinct patient populations of men with CRPC: 1) non-metastatic treatment-naïve CRPC; 2) mCRPC treatment-naïve (tx-naïve); and 3) mCRPC abiraterone acetate pre-treated (AA). Preliminary results for the 2 cohorts of patients with metastatic CRPC are presented here. METHODS All patients had metastatic CRPC with progressive disease based on rising PSA and/or imaging. No prior chemotherapy for metastatic prostate cancer was allowed. Patients on the AA pre-treated cohort had to have been treated with AA for at least 6 months. All patients received ARN-509 at the recommended Phase II dose of 240 mg/day (Rathkopf et al, GU ASCO 2012). The primary endpoint was PSA response rate at 12 weeks according to the Prostate Cancer Working Group 2 Criteria in each of the treatment groups. Secondary endpoints included safety, time to PSA progression and objective response rates. PSA assessments were collected every 4 weeks and tumor imaging was performed every 16 weeks. RESULTS A total of 46 patients were enrolled: 25 on the tx-naïve and 21 on the post-AA cohorts. The combined median age was 68 (range 48-91) and at baseline, patients presented with ECOG performance status 0 (57%), Gleason Score 8-10 (52%), and median PSA of 14.7 (tx-naïve) and 58.4 (post-AA) ng/mL. All patients received prior treatment with a LHRH analog with or without a first-generation anti-androgen. To date, 15 patients discontinued the study due to disease progression (11), adverse events (2) and consent withdrawn (2). The most common treatment-related adverse events (AE) were fatigue (30%), abdominal pain (24%), nausea (22%), and diarrhea (17). There was only 1 treatment-related Grade 3 AE of abdominal pain. At 12 weeks, the PSA response was 88% (tx-naïve) and 29% (post-AA). CONCLUSIONS In men with mCRPC, ARN-509 is safe and well tolerated, with robust PSA response in the tx-naïve cohort. Post-AA data suggests that ARN-509 has activity in a subset of patients that developed resistance to abiraterone acetate. CLINICAL TRIAL INFORMATION NCT01171898.

Safety and antitumor activity of apalutamide (ARN-509) in metastatic castration-resistant prostate cancer with and without prior abiraterone acetate and prednisone

Purpose: To evaluate the efficacy of apalutamide before or after treatment with abiraterone acetate and prednisone (AAP) in patients with progressive metastatic castration-resistant prostate cancer (mCRPC). Experimental Design: Two cohorts were studied: AAP-naïve and post-AAP patients who had received ≥6 months of AAP. Patients had progressive mCRPC per rising prostate-specific antigen (PSA) and/or imaging, without prior chemotherapy exposure. All received apalutamide 240 mg/day. Primary endpoint was ≥50% decline in 12-week PSA according to Prostate Cancer Working Group 2 criteria. Secondary endpoints included time to PSA progression and time on treatment. Results: Forty-six patients enrolled in the AAP-naïve (n = 25) and post-AAP (n = 21) cohorts. The 12-week PSA response rate was 88% (22/25) and 22% (4/18), median time to PSA progression was 18.2 months [95% confidence interval (CI), 8.3 months–not reached) and 3.7 months (95% CI, 2.8–5.6 months), and median time on treatment 21 months (range, 2.6–37.5) and 4.9 months (range, 1.3–23.2), for the AAP-naïve and post-AAP cohorts, respectively. Eighty percent (95% CI, 59–93) and 64% (95% CI, 43–82) of AAP-naïve and 43% (95% CI, 22–66) and 10% (95% CI, 1–30) of post-AAP patients remained on treatment for 6+ and 12+ months, respectively. Common treatment-emergent adverse events in both cohorts were grade 1 or 2 fatigue, diarrhea, nausea, and abdominal pain. Conclusions: Apalutamide was safe, well tolerated, and demonstrated clinical activity in mCRPC, with 80% of AAP-naïve and 43% of post-AAP patients, remaining on treatment for 6 months or longer. Clin Cancer Res; 23(14); 3544–51. ©2017 AACR.

Two Year Durability after Crossover to the Prostatic Urethral Lift from Randomized, Blinded Sham

To evaluate the 24‐month effectiveness of the prostatic urethral lift (PUL) procedure in men with lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH) assessed through a crossover study.

Selective estrogen receptor alpha agonist GTx-758 decreases testosterone with reduced side effects of androgen deprivation therapy in men with advanced prostate cancer

BACKGROUND A need remains for new therapeutic approaches for men with advanced prostate cancer, particularly earlier in the disease course. OBJECTIVE To assess the ability of an oral selective estrogen receptor α agonist (GTx-758) to lower testosterone concentrations compared with leuprolide while minimizing estrogen deficiency-related side effects of androgen-deprivation therapy. DESIGN, SETTING, AND PARTICIPANTS Hormone-naive advanced prostate cancer patients were randomized to oral GTx-758 1000 mg/d, 2000 mg/d, or leuprolide depot. INTERVENTION GTx-758 and leuprolide. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The primary end point was the proportion of patients achieving total testosterone ≤ 50 ng/dl by day 60. Secondary end points included serum free testosterone, prostate-specific antigen (PSA), sex hormone-binding globulin, hot flashes, bone turnover markers, and insulin-like growth factor (IGF)-1 levels. RESULTS AND LIMITATIONS Of 159 randomized patients, leuprolide reduced total testosterone to ≤ 50 ng/dl in a greater proportion of patients than GTx-758 by day 60 (43.4%, 63.6%, and 88.2% of subjects receiving GTx-758 1000 mg [p<0.001], GTx-758 2000 mg [p=0.004], and leuprolide, respectively). GTx-758 reduced free testosterone and PSA earlier and to a greater degree than leuprolide. GTx-758 led to fewer hot flashes, decreases in bone turnover markers, and alterations in IGF-1 compared with leuprolide. A higher incidence of venous thromboembolic events (VTEs) was seen with GTx-758 (4.1%) compared with leuprolide (0.0%). CONCLUSIONS Although leuprolide reduced total testosterone to ≤ 50 ng/dl in a greater proportion of patients compared with GTx-758, GTx-758 was superior in lowering free testosterone and PSA. GTx-758 reduced estrogen deficiency side effects of hot flashes, bone loss, and insulin resistance but with a higher incidence of VTEs. PATIENT SUMMARY This paper reports findings that leuprolide lowered total testosterone more than GTx-758 but that GTx-758 lowered free testosterone and prostate-specific antigen more than leuprolide. GTx-758 also reduced estrogen deficiency side effects, albeit at a higher rate of vascular events. TRIAL REGISTRATION Clinicaltrials.gov identifier NCT01615120.

Use of intravesical valrubicin in clinical practice for treatment of nonmuscle-invasive bladder cancer, including carcinoma in situ of the bladder

Objectives: The objective was to conduct a US multicenter, retrospective medical record study examining the effectiveness, safety, and patterns of use of valrubicin for treatment of nonmuscle-invasive bladder cancer (NMIBC) by clinicians since the 2009 reintroduction of valrubicin. Methods: Patients ≥ 18 years with NMIBC who received had one or more instillations of valrubicin (October 2009– September 2011) were eligible. The primary endpoint was event-free survival (EFS). Safety and tolerability were also assessed. Results: The medical records of 113 patients met the inclusion criteria; 100 patients (88.5%) completed valrubicin treatment. The median age was 75 years (range 42–95 years). The median NMIBC duration was 31 months since diagnosis: 51.3% (58/113) had carcinoma in situ (CIS) alone, and 31.9% (36/113) had unspecified NMIBC. Most patients, 94.7% (107/113), had more than three valrubicin instillations and 70.8% (80/113) completed a full course. The EFS rate (95% confidence interval) was 51.6% (40.9–61.3%), 30.4% (20.4–41.1%), and 16.4% (7.9–27.5%) at 3, 6, and 12 months, respectively. Median time to an event was 3.5 (2.5–4.0) months after the first valrubicin instillation. Local adverse reactions (LARs) were experienced by 49.6% (56/113) of patients; most LARs were mild (93.6%). The most frequent LARs were hematuria, pollakiuria, micturition urgency, bladder spasm, and dysuria. In total, 4.4% (5/113) of patients discontinued valrubicin because of adverse events or LARs. Conclusions: Data from the present retrospective study are consistent with previous prospective clinical trials that demonstrated valrubicin effectiveness and tolerability for select patients with CIS, before considering cystectomy. Additional prospective studies are warranted to evaluate valrubicin safety and efficacy in the broader patient population with NMIBC.

Clinical utility of the Prostate Health Index ( phi ) for biopsy decision management in a large group urology practice setting

BackgroundDeciding when to biopsy a man with non-suspicious DRE findings and tPSA in the 4–10 ng/ml range can be challenging, because two-thirds of such biopsies are typically found to be benign. The Prostate Health Index (phi) exhibits significantly improved diagnostic accuracy for prostate cancer detection when compared to tPSA and %fPSA, however only one published study to date has investigated its impact on biopsy decisions in clinical practice.MethodsAn IRB approved observational study was conducted at four large urology group practices using a physician reported two-part questionnaire. Physician recommendations were recorded before and after receiving the phi test result. A historical control group was queried from each sites electronic medical records for eligible men who were seen by the same participating urologists prior to the implementation of the phi test in their practice. 506 men receiving a phi test were prospectively enrolled and 683 men were identified for the historical control group (without phi). Biopsy and pathological findings were also recorded for both groups.ResultsMen receiving a phi test showed a significant reduction in biopsy procedures performed when compared to the historical control group (36.4% vs. 60.3%, respectively, P < 0.0001). Based on questionnaire responses, the phi score impacted the physician’s patient management plan in 73% of cases, including biopsy deferrals when the phi score was low, and decisions to perform biopsies when the phi score indicated an intermediate or high probability of prostate cancer (phi ≥36).Conclusionsphi testing significantly impacted the physician’s biopsy decision for men with tPSA in the 4–10 ng/ml range and non-suspicious DRE findings. Appropriate utilization of phi resulted in a significant reduction in biopsy procedures performed compared to historical patients seen by the same participating urologists who would have met enrollment eligibility but did not receive a phi test.

eRADicAte: A Prospective Evaluation Combining Radium-223 Dichloride and Abiraterone Acetate Plus Prednisone in Patients With Castration-Resistant Prostate Cancer

Background Multiple castration‐resistant prostate cancer (CRPC) therapies are approved by the United States Food and Drug Administration. Radium‐223 dichloride (Ra‐223) with abiraterone acetate plus prednisone have different mechanisms of action and distinct off‐target side‐effect profiles. We prospectively investigated their combined safety, tolerability, and patient‐reported outcome measures. Patients and Methods eRADicAte, an investigator‐initiated, phase II trial, studied 31 patients with metastatic CRPC, from 5 United States uro‐oncology research sites. Patients completed 6 cycles of Ra‐223 with concurrent abiraterone therapy. Quality of life and pain were assessed using the Functional Assessment of Cancer Therapy‐Prostate and the Brief Pain Inventory‐Short Form questionnaires and their subscales; we reported the number of subjects meeting standardized criteria for clinically meaningful improvements on each scale. Safety assessment included Eastern Cooperative Oncology Group performance status, laboratory changes, opioid use, radiographic responses, and adverse events (AEs). Results Twenty of 31 (65%) experienced positive clinically meaningful improvement changes on the Functional Assessment of Cancer Therapy‐Prostate, and 25 (81%) of 31 on the Prostate Cancer Subscale. Eighteen (58%) of 31 demonstrated reduced pain intensity and 12 (39%) of 31 demonstrated reduction of pain interference in their lives. At baseline, subjects averaged 11.6 ± 2.8 bone lesions; at the end of treatment, subjects averaged 5.6 ± 2.4 bone lesions (P = .0002). The most frequent AEs were diarrhea (17%), nausea (17%), and fatigue (14%). There were 6 serious AEs; 1 led to study withdrawal. Conclusions Patients experienced clinically meaningful improvements in quality of life and pain, without unexpected adverse toxicities. Phase III combination trials of Ra‐223 with novel oral hormonal agents are ongoing to further evaluate radiographic progression and overall survival benefit. Micro‐Abstract This is the first study to prospectively evaluate the combined use of radium‐223 dichloride and a novel oral hormonal therapy, abiraterone acetate, in men with metastatic castration‐resistant prostate cancer. The eRADicAte study showed that patients with metastatic castration‐resistant prostate cancer experienced clinically meaningful improvements in quality of life with decreased pain, reduction in bone lesions, and an acceptable safety and toxicity profile.

Effect of GTx-758, an ERα agonist, on serum-free testosterone and serum PSA in men with advanced prostate cancer.

104 Background: Androgen deprivation therapy (ADT) improves disease-free survival in men with advanced prostate cancer, but patients develop castrate resistant prostate cancer (CRPC); one of the causes of which is ineffective castration. Total serum testosterone (T) does not accurately predict prostatic levels of T. Further reduction of androgens in men with CRPC can result in improvement of survival. Herein we compare the effects GTx-758 an oral, selective estrogen receptor alpha (ERα) agonist versus leuprolide on total and free (unbound) serum T levels in men with advanced prostate cancer. METHODS In Phase II studies, men with advanced prostate cancer (n=164) received 1000 mg or 2000 mg GTx-758 daily or Lupron Depot (4 month), while men with CRPC (n=9) received 2000 mg GTx-758 daily. Serum concentrations of total T, free T, SHBG and PSA were determined at baseline and during treatment. RESULTS In ADT naïve advanced prostate cancer patients, 28 days of 1000 mg or 2000 mg daily GTx-758 or Lupron therapy castrated (T<50ng/dL) 50, 31 and 100% of patients, reducing mean serum total T in castrated patients to 23±14, 19±9 and 14±7 ng/dL, respectively. However, treatment with 1000 mg or 2000 mg GTx-758 daily reduced mean free T levels to a greater extent (0.9±0.7 and 0.7±0.7 pg/mL, respectively) than Lupron (1.7±1.1 pg/mL). Changes in PSA at 28 days were more closely associated with the observed changes in free T, with reductions of 74, 72 and 56% for 1000 mg, 2000 mg doses of GTx-758 and Lupron, respectively. In CRPC patients, 2000 mg GTx-758 daily did not further reduce serum total T levels, but did result in free T reductions and PSA decreases from baseline following 15 days of therapy in all of the men maintained on ADT with LHRH agonists alone. CONCLUSIONS Although GTx-758 and LHRH based ADT both reduce total serum T and PSA levels in ADT naïve advanced prostate cancer patients, free T was rapidly reduced to a greater degree in the GTx-758 treated patients. In men with CRPC, GTx-758 therapy resulted in significant reductions in free T and resultant PSA declines. The ability of GTx-758 to reduce free T provides a unique mechanism to treat men with advanced prostate cancer and CRPC. CLINICAL TRIAL INFORMATION NCT01326312.

Abstract CT239: ARN-509 in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with abiraterone acetate (AA)

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Background: ARN-509 is a novel second-generation antiandrogen that binds directly to the ligand-binding domain of the androgen receptor (AR), impairing AR nuclear translocation and DNA binding to the androgen response element. Phase 2 of a multicenter phase 1/2 study evaluates ARN-509 activity in 3 distinct patient populations of men with CRPC: 1) nonmetastatic chemotherapy-naive CRPC; 2) chemotherapy-naive mCRPC; 3) mCRPC post-AA treatment. Study ARN-509-001 is the first to prospectively examine response to novel second-generation antiandrogens post-AA treatment. We present the results of the post-AA treated cohort, as of July 2013. Methods: All patients had mCRPC with progressive disease based on rising prostate-specific antigen (PSA) and/or imaging. No prior chemotherapy for CRPC was allowed. Patients in the AA-pretreated cohort had to have been treated with AA for at least 6 months. All patients received ARN-509 at the recommended phase 2 dose of 240 mg/d (Rathkopf et al. J Clin Oncol. 2013). The primary end point was PSA response at 12 weeks according to the Prostate Cancer Working Group 2 criteria. Secondary end points included safety, time to PSA progression, and objective response rates. PSA assessments were collected every 4 weeks and tumor imaging was performed every 12 weeks. Results: By July 2013, 21 patients were enrolled and treated in the post-AA cohort. The median age was 67 years (range 48-83). At baseline, 62% of patients had an Eastern Cooperative Oncology Group performance status 0, and 29% had a Gleason score ≥ 8; median PSA was 58.4 ng/mL. Median duration on ARN-509 treatment post AA was 5.6 months (range 1.9-16.7). At 12 weeks, 24% (5/21) of patients had ≥ 50% decline in PSA from baseline. Median time to PSA progression was 16 weeks (95% confidence interval, 12-31 weeks). The best objective response was stable disease in 4 (36%) patients. Patients discontinued the study due to disease progression (n = 13), adverse events (n = 2), consent withdrawn (n = 1), and other reasons (n = 4). The most common treatment-related adverse events were fatigue (n = 11), nausea (n = 5), and diarrhea (n = 3). Conclusions: In men with mCRPC, post-AA treatment, ARN-509 is safe and well tolerated, with modest activity in a subset of patients who develop resistance to AA. Clinical trial information: [NCT01171898][1]. Citation Format: Dana E. Rathkopf, Emmanuel S. Antonarakis, Neal D. Shore, Ronald Tutrone, Joshi J. Alumkal, Charles J. Ryan, Mansoor N. Saleh, Ralph J. Hauke, Rajesh Bandekar, Edna Chow Maneval, Carla de Boer, Mary Todd, Margaret K. Yu, Howard I. Scher. ARN-509 in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with abiraterone acetate (AA). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT239. doi:10.1158/1538-7445.AM2014-CT239 [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01171898&atom=%2Fcanres%2F74%2F19_Supplement%2FCT239.atom